Urine exosomes as biomarkers in bladder cancer diagnosis and prognosis: From functional roles to clinical significance.

Bladder cancer is one of the top ten most common cancers and top ten causes of cancer death globally. 5-year survival rates have decreased in Australia from 66% to 55% in the past three decades. The current gold standard for diagnosis is cystoscopy. However, cystoscopies are an invasive and health-resource intensive procedure which has sub-optimal sensitivity for flat lesions such as CIS (carcinoma in situ) and low specificity for differentiating inflammation from cancer - hence requiring biopsies under anesthesia. Frequent and life-long surveillance cystoscopy is required for most patients since there are high rates of progression and local recurrence in high-risk non-muscle invasive cancer (NMIBC) as well as poor outcomes associated with delayed detection of muscle-invasive bladder cancer (MIBC). There is an unmet need for a non-invasive test to provide better discrimination and risk-stratification of bladder cancer which could aid clinicians by improving patient selection for cystoscopy; enhanced risk stratification methods may guide the frequency of surveillance cystoscopies and inform treatment choices. Exosomes, which are nano-sized extracellular vesicles containing genetic material and proteins, have been shown to have functional roles in the development and progression of bladder cancer. Exosomes have also been demonstrated to be a robust source of potential biomarkers for bladder cancer diagnosis and prognosis and may also have roles as therapeutic agents. In this review, we summarize the latest evidence of biological roles of exosomes in bladder cancer and highlight their clinical significance in bladder cancer diagnosis, surveillance and treatment.

Differentiation of renal masses with multi-parametric MRI: the de Silva St George classification scheme.

PURPOSE: To develop a system for multi-parametric MRI to differentiate benign from malignant solid renal masses and assess its accuracy compared to the gold standard of histopathological diagnosis. METHODS: This is a retrospective analysis of patients who underwent 3 Tesla mpMRI for further assessment of small renal tumours with specific scanning and reporting protocol incorporating T2 HASTE signal intensity, contrast enhancement ratios, apparent diffusion coefficient and presence of microscopic/macroscopic fat. All MRIs were reported prior to comparison with histopathologic diagnosis and a reporting scheme was developed. 2 × 2 contingency table analysis (sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)), Fisher Exact test were used to assess the association between suspicion of malignancy on mpMRI and histopathology, and descriptive statistics were performed. RESULTS: 67 patients were included over a 5-year period with a total of 75 renal masses. 70 masses were confirmed on histopathology (five had pathognomonic findings for angiomyolipomas; biopsy was therefore considered unethical, so these were included without histopathology). Three patients were excluded due to a non-diagnostic result, non-standardised imaging and one found to be an organising haematoma rather than a mass. Therefore 72 cases were included in analysis (in 64 patients, with seven patients having multiple tumours). Unless otherwise specified, all further statistics refer to individual tumours rather than patients. 52 (72.2%) were deemed 'suspicious or malignant' and 20 (27.8%) were deemed 'benign' on mpMRI. 51 cases (70.8%) had renal cell carcinoma confirmed. The sensitivity, NPV, specificity and PPV for MRI for detecting malignancy were 96.1%, 90%, 85.7% and 94.2% respectively, Fisher's exact test demonstrated p < 0.0001 for the association between suspicion of malignancy on MRI and histopathology. CONCLUSION: The de Silva St George classification scheme performed well in differentiating benign from malignant solid renal masses, and may be useful in predicting the likelihood of malignancy to determine the need for biopsy/excision. Further validation is required before this reporting system can  be recommended for clinical use.

The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI) is validated for the detection of clinically significant prostate cancer (csPCa), although patients with negative/equivocal MRI undergo biopsy for false negative concerns. In addition, 68Ga-PSMA-11 positron emission tomography/computed tomography (prostate-specific membrane antigen [PSMA]) may also identify csPCa accurately. OBJECTIVE: This trial aimed to determine whether the combination of PSMA + MRI was superior to MRI in diagnostic performance for detecting csPCa. DESIGN, SETTING, AND PARTICIPANTS: A prospective multicentre phase II imaging trial was conducted. A total of 296 men were enrolled with suspected prostate cancer, with no prior biopsy or MRI, recent MRI (6 mo), and planned transperineal biopsy based on clinical risk and MRI. In all, 291 men underwent MRI, pelvic-only PSMA, and systematic ± targeted biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Sensitivity, specificity, and predictive values (negative predictive value [NPV] and positive predictive value) for csPCa were determined for MRI, PSMA, and PSMA + MRI. PSMA + MRI was defined as negative for PSMA negative Prostate Imaging Reporting and Data System (PI-RADS) 2/3 and positive for either MRI PI-RADS 4/5 or PSMA positive PI-RADS 2/3; csPCa was any International Society of Urological Pathology (ISUP) grade group ≥2 malignancy. RESULTS AND LIMITATIONS: Of the patients, 56% (n = 162) had csPCa; 67% had PI-RADS 3-5, 73% were PSMA positive, and 81% were combined PSMA + MRI positive. Combined PSMA + MRI improved NPV compared with MRI alone (91% vs 72%, test ratio = 1.27 [1.11-1.39], p < 0.001). Sensitivity also improved (97% vs 83%, p < 0.001); however, specificity was reduced (40% vs 53%, p = 0.011). Five csPCa cases were missed with PSMA + MRI (four ISUP 2 and one ISUP 3). Of all men, 19% (56/291) were PSMA + MRI negative (38% of PI-RADS 2/3) and could potentially have avoided biopsy, risking delayed csPCa detection in 3.1% men with csPCa (5/162) or 1.7% (5/291) overall. CONCLUSIONS: PSMA + MRI improved NPV and sensitivity for csPCa in an MRI triaged population. Further randomised studies will determine whether biopsy can safely be omitted in men with a high clinical suspicion of csPCa but negative combined imaging. PATIENT SUMMARY: The combination of magnetic resonance imaging (MRI) + prostate-specific membrane antigen positron emission tomography reduces false negatives for clinically significant prostate cancer (csPCa) compared with MRI, potentially allowing a reduction in the number of prostate biopsies required to diagnose csPCa.

The diagnostic utility of diffusion weighted MRI imaging and ADC ratio to distinguish benign from malignant renal masses: sorting the kittens from the tigers.

BACKGROUND: MRI is playing an increasing role in risk stratification and non-invasive diagnosis of the undifferentiated small renal mass. This study was designed to assess the reliability of MRI in diagnostic evaluation of renal masses, specifically characterising lesions with diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) values. METHODS: This is a retrospective analysis of patients undergoing MRI as part of their clinical workup for a renal mass suspicious for renal cell carcinoma (RCC) on CT or ultrasound followed by biopsy and/or surgical excision. All cases were conducted on 3 Tesla MRI, with conventional breath-held sequences, DWI and dynamic contrast enhanced phases. Tumour regions of interest were evaluated on ADC maps and compared with T2 weighted and post-contrast images. RESULTS: Of the 66 renal tumours included, 33 (50.0%) were Clear Cell RCC, 11 (16.7%) were Oncocytoma, nine (13.6%) were Angiomyolipoma (AML), nine (13.6%) were Papillary RCC and four (6.1%) were Chromophobe RCC. Oncocytoma had the largest ADC values, significantly larger than AMLs and all RCC subtypes (p < 0.001). The average ADC value was also significantly larger in Clear Cell RCCs compared to AMLs, and other RCC subtypes (p < 0.001). CONCLUSIONS: MRI with DWI/ADC imaging may aid the differentiation of oncocytomas from RCCs and stratify RCC subtypes, Further studies are required to validate these findings. TRIAL REGISTRATION: Not applicable/retrospective study.

Chemical shift imaging in the identification of those renal tumours that contain microscopic fat and the utility of multiparametric MRI in their differentiation.

INTRODUCTION: The aim of this study was to assess the qualitative and MRI findings of renal tumours, to determine which lesions contain microscopic fat, one of the potential differentiating factors between tumour types. METHODS: 73 patients who underwent 3 Tesla MRI including chemical shift imaging, with subsequent biopsy or excision for histopathological diagnosis, were included in the study. The images were reviewed for a decrease in signal intensity (SI) on the opposed phase compared with the in-phase gradient echo T1 images, indicating the presence of microscopic fat. The chemical shift index was then calculated as a percentage of SI change and compared with the pathological diagnosis. RESULTS: In total, 38 (52%) of lesions demonstrated a decrease in SI, consistent with microscopic fat. Microscopic fat was found in 28 (80%) clear cell renal cell carcinomas (RCCs), 6 (66.7%) angiomyolipomas, 2 (20%) papillary RCCs, 1 (20%) chromophobe RCC and 1 (9.1%) oncocytoma. Pairwise comparison of means indicated that the amount of microscopic fat was significantly larger only for angiomyolipomas compared with clear cell RCCs (P < 0.001) and other renal lesions (P < 0.001). CONCLUSIONS: A decrease in SI on opposed phase compared with in-phase chemical shift imaging favours the diagnosis of either clear cell RCC or an angiomyolipoma. When combined with other parameters in mpMRI, this may aid differentiation of benign from malignant tumours and differentiation of aggressive from indolent RCC subtypes. This may be of value where biopsy is non-diagnostic, not feasible due to location or in high-risk patients.

Frequency of Angiomyolipomas Among Echogenic Nonshadowing Renal Masses (> 4 mm) Found at Ultrasound and the Utility of MRI for Diagnosis.

OBJECTIVE: The purpose of this study is to evaluate what percentage of echogenic nonshadowing renal lesions larger than 4 mm found at ultrasound are angiomyolipomas (AMLs) and to review how to diagnose AMLs, with particular emphasis on the increasing role played by MRI. MATERIALS AND METHODS: The study data were obtained at a single institution over a period of 45 months. Although some patients were being reviewed for specific symptoms, such as hematuria, pain, or recurrent urinary tract infections, most of the findings were incidental. Follow-up data on 158 lesions in 132 patients were available. Confirmation of diagnosis was made with follow-up imaging or with histopathologic examination. RESULTS: Ninety-eight (62.0%) of the lesions were AMLs, eight (5.1%) were renal cell carcinomas, three (1.9%) were oncocytomas, 17 (10.8%) were artifacts, seven (4.4%) were fat, five (3.2%) were calculi, another eight (5.1%) were scars, and 12 (7.6%) were complicated cysts. The mean age of patients with AML was significantly lower than that of patients without AML (61.71 [SD, 13.25] years vs 68.80 [SD, 17.85] years; p = 0.005). There was a female association with AMLs (p < 0.001). CONCLUSION: Echogenic nonshadowing renal lesions larger than 4 mm seen at ultrasound should not be assumed to represent an AML without follow-up because a percentage of renal cell carcinomas will be missed. Although certain ultrasound features can be useful in differentiating an AML from a renal cell carcinoma and CT is frequently diagnostic, an understanding of MRI is important because it can potentially detect lipid-poor AMLs.

Cancer control, continence, and potency after laparoscopic radical prostatectomy beyond the learning and discovery curves.

PURPOSE: To investigate the results of laparoscopic radical prostatectomy (LRP) beyond the learning and discovery curves of 700 patients previously reported by the authors for potency. PATIENTS AND METHODS: Five hundred consecutive patients underwent LRP during a 28-month period with a minimum follow-up of 12 months. Median age (with range) = 61.0 (33-76) years; prostate-specific antigen level = 7.0 (1-37); biopsy Gleason sum = 7 (4-10). Clinical stage was T1 in 41.0%, T2 in 54.2%, and T3 in 4.8%. Nerve preservation (NP) was performed bilaterally in 57.9%, unilaterally in 15.3%, and on neither side in 26.8%. RESULTS: Median operative time was 157 (91-331) minutes, with no conversions or intraoperative blood transfusions; 0.4% of patients received a transfusion postoperatively, and 4.2% had complications. There were no rectal injuries. The overall positive margin rate was 13.0% and correlated with pathologic parameters. At a minimum of 1 year follow-up (mean=13.5 (12-36) mos), overall survival was 100%, and biochemical disease-free survival was 98.8%. The pad-free rate was 97.4%. Potency (International Index of Erectile Function-5 score ≥17) at a mean follow-up of 13.5 months in previously potent men in their 4th, 5th, 6th, and 7th decades after bilateral NP was 100.0%, 91.8%, 82.9%, and 60.0% and after unilateral NP was 100%, 66.7%, 50.1%, and 0.0%. Overall potency after bilateral neurovascular bundle NVB preservation was 86.9%. CONCLUSION: LRP is capable of matching or exceeding the best results for open radical prostatectomy and robot-assisted radical prostatectomy when performed by an experienced surgeon in a high-volume setting. These results suggest that the method used to perform radical prostatectomy is a less important determinant of success than surgical experience.